title: Hepatic basolateral efflux contributes significantly to rosuvastatin disposition II: characterization of hepatic elimination by basolateral, biliary, and metabolic clearance pathways in rat isolated perfused liver.
abstract: Basolateral efflux clearance (CLBL) contributes significantly to rosuvastatin (RSV) elimination in sandwich-cultured hepatocytes (SCH). The contribution of CLBL to RSV hepatic elimination was determined in single-pass isolated perfused livers (IPLs) from wild-type (WT) and multidrug resistance-associated protein 2 (Mrp2)-deficient (TR(-)) rats in the absence and presence of the P-glycoprotein and breast cancer resistance protein (Bcrp) inhibitor, elacridar (GF120918); clearance values were compared with SCH. RSV biliary clearance (CLBile) was ablated almost completely by GF120918 in TR(-) IPLs, confirming that Mrp2 and Bcrp primarily are responsible for RSV CLBile. RSV appearance in outflow perfusate was attributed primarily to CLBL, which was impaired in TR(-) IPLs. CLBL was ≈ 6-fold greater than CLBile in the linear range in WT IPLs in the absence of GF120918. Recovery of unchanged RSV in liver tissue increased in TR(-) compared with WT (≈ 25 versus 6% of the administered dose) due to impaired CLBL and CLBile. RSV pentanoic acid, identified by high-resolution liquid chromatography-tandem mass spectroscopy, comprised ≈ 40% of total liver content and ≈ 16% of the administered dose in TR(-) livers at the end of perfusion, compared with ≈ 30 and 3% in WT livers, consistent with impaired RSV excretion and "shunting" to the metabolic pathway. In vitro-ex vivo extrapolation between WT SCH and IPLs (without GF120918) revealed that uptake clearance and CLBL were 4.2- and 6.4-fold lower, respectively, in rat SCH compared with IPLs; CLBile translated almost directly (1.1-fold). The present IPL data confirmed the significant role of CLBL in RSV hepatic elimination, and demonstrated that both CLBL and CLBile influence RSV hepatic and systemic exposure.
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina (N.D.P., B.C.F., K.L.R.B.); and Department of Pathology (A.S.B.) and Curriculum in Toxicology (R.N.H., K.L.R.B.), School of Medicine, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Pfeifer
authors.forename: Arlene S
authors.initials: AS
authors.lastname: Bridges
authors.forename: Brian C
authors.initials: BC
authors.lastname: Ferslew
authors.forename: Rhiannon N
authors.initials: RN
authors.lastname: Hardwick
authors.forename: Kim L R
authors.initials: KL
authors.lastname: Brouwer
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D001646:Bile / Q000378:metabolism; D001659:Biliary Tract / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D005464:Fluorobenzenes / Q000097:blood / Q000493:pharmacokinetics*; D022781:Hepatocytes / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D010421:Pentanoic Acids / Q000378:metabolism; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry
chemical_list: D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D002352:Carrier Proteins; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010421:Pentanoic Acids; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium